Epigenetic modifier Smchd1 maintains a normal pool of long-term repopulating hematopoietic stem cells in mice I

We have used a conditional mouse model to investigate the role of Smchd1 specifically in hematopoiesis. We found that Smchd1-deleted mice have an altered hematopoietic stem and progenitor cell (HSPC) compartment with reduced repopulating capacity in competitive bone marrow transplantation assays and the gradual loss of adult hematopoietic stem cells (HSCs) with age, suggesting a role for Smchd1 in the maintenance of long-term adult HSCs. The phenotype was more pronounced in female Smchd1-deleted mice, which showed a more severe reduction in HSCs with age, as well as depleted numbers of B cell lymphocytes. Gene expression profiling of Smchd1 deficient HSCs and B cells revealed several known and novel Smchd1-sensitive genes, a significant disruption to X-linked gene expression, although this was not widespread upregulation of X-linked genes in female cells. These data show Smchd1 as a new regulator of long-term HSCs whose effects are more profound in females. Overall design: We have compared Smchd1-deleted LT-HSCs with controls that are heterozygous for the same Smchd1 deletion. Here was have sorted duplicate or triplicate wells of 50-100 Lin-ckit+ Sca1+ Flt3- CD48- CD150+ LT-HSCs from the bone marrow of n = 3 Smchd1-het (control) females, n = 3 Smchd1-del (test) females, n= 3 Smchd1-het males and n = 2 Smchd1-del males.